Antibiotic

1
Antibiotic Stewardship
Cliff Wlodaver, MD Chris May, Pharm D
2

• Antibiotics the root cause for resistance
• Darwinism
• Alexander Flemming
• Louis Weinstein
• Native American wisdom

3
Goal of Antibiotic Stewardship

• Attack the root cause by fine tuning antibiotic
  use
• Condense clinical infectious disease,
• ad absurdum
• Create mini-ID specialists,
• by recipe
• Practicality?

4
Agenda

• Basics (theory)
• Specifics (practice)
• Physician/administration approval
• Physician response
• Measurement/reporting
• Cost implications
• BREAK
• Clinical vignettes
• Summary/Implementation
• Questions/Discussion

5
What is Antibiotic Stewardship?

• A program that encourages judicious (vs
  injudicious) use of antibiotics.

6

• Antibiotics are relatively so effective,
  non-toxic and inexpensiveso easy to usethat
  they are
• prone to misuse
• When the diagnosis is uncertain, antibiotics
  are often prescribed, viewed as a medical
  necessity (drugs of fear) but theyre not
  benign
• We need a paradigm shift

7

• Man has an inborn craving for medicinethe
  desire to take medicine is one feature which
  distinguishes man, the animal, from his fellow
  creatures.
• Sir William Osler
• Teaching and Thinking,
• in Aequanimitas

8

• Risk Perception and Inappropriate
  Antimicrobial Use Yes, It can Hurt
• Powers. Clin Infect Dis 2009481350-3

9
Emergency Department Visits for Adverse Drug
Reactions

• Sheab et al. Clin Infect Dis 2008 4773543

10
Stewardship strives to fine tune antibiotic Rx
in regards to

• Efficacy/Toxicity
• Resistance-induction/C. difficile
• Cost
• Appropriate discontinuation

11
What are its Limitations?

• Its difficult dangerous outrageous to
  practice clinical infectious diseases with
  limited information
• Select cases very carefully
• Primum non nocere
• Practicality?

12
Does it work?
13
Outcomes of the University of Pennsylvania
Hospitals Antibiotic Stewardship Program
Gross. et al. Clin Infect Dis. 2001 289-295.
14
MRSA and C. difficille Rates After Implementation
of an Antibiotic Stewardship Program
Fowler et al. JAC 2007 59, 990995
15
Effect of an Antibiotic Stewardship Program on
the Rate of Resistant Enterobacter Infections
Carling et al. Infect Control Hosp Epidemiol
200324699-706).
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Recommended by

• Collaborative
• Drs. Perl, Bratzler, CW
• IDSA
• Dellit et al. Clin Infect Dis 2007 44 159-77
• CDC
• Tattevin et al. Emerg Infect Dis 2009 15 953-5
• Practiced regularly

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How does it work?

• A pharmacist, par excellence, or someone else
  reviews patients on antibiotics and makes
  recommendations, prn overseen by a PHYSICIAN
  CHAMPION, an ID-trained physician, when
  available
• Training
• Contact the prescribing physician
• Telephone call
• Announce non-threatening dont interrupt
  (leave message)
• Chart notation
• Rx change implemented
• Physician
• Pharmacist, verbal order

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Common Interventions

• Allergies, interactions
• Dosing
• IV-to-po switch
• Redundancy
• Cost
• Empiric Rx, then Streamlining, (de-escalation)
• When not to use antibiotics in the first place
• Discontinuation

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Common InterventionsSome are so evident that
they should be/are automatic

• Allergy, e.g.
• PCN PCN-cephalosporin cross-reactivity
• Drug-drug interactions, e.g.
• Vanco-gentamicin synergistic toxicity
• Rifampins effect on hepatic drug metabolism
• Coumadin
• Address toxicities, e.g.
• Renal
• Aminoglycosides
• Hepatic

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• Dosing
• Cefazolin q8h
• Ceftriaxone q24h
• Aminoglycosides q24h
• Levels
• Aminoglycosides
• Vancomycin

21
Vancomycin Dosing

• MRSA epidemic
• MIC creep
• Dosing reviewed
• Traditional 1gm q12 h
• New recommendation 15mg/kg q12 h
• (ATS/IDSA. Am J Respir Crit
  Care Med 2005171388-416)
• Nomogram for renal impairment

22
Vancomycin Levels

• Therapeutic and toxic levels uncertain (CID 94)
• Resistance has led to aiming for trough of 15-20
  (ATS/IDSA)
• And this has led to nephrotoxicity
• Measuring levels often leads to under-dosing
• Management options
• Dont do levels
• Exceptions
• 1. Patients receiving vanco/aminoglycoside
  combination
• 2. Anephric patients undergoing dialysis
• 3. Patients with rapidly changing renal function
• 4. Patients receiving higher-than-usual doses
• Use a different antibiotic

23
IV-to-po Switch

• Criteria
• Afebrile, WBC normalized
• Maybe the patient doesnt need any further
  antibiotics in the first place
• Intact GI tract, i.e. no N/V/D
• Oral bioavailability, e.g. quinolones
• Patient can often go home, on po AB,
• without further in-hospital observation
• Ramirez
  et al. Arch Intern Med 2001 16184850

24
IV removal 1 defense vs BSI

• Requirement for hospitalization
• intensity of care criterion
• Leave in place
• just in case
• what if?

25
Antibiotic Redundancy

• vs Anaerobes PCN/pcn-ase inhibitor (e.g. Zosyn,
  Unasyn) or carbapenem (e.g. Primaxin) Flagyl
• vs C. diff po Flagyl po vanco
• Etc.

26
Promoting use of less costly alternativesCascade
reporting
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Cost IssuesTherapeutic Substitutions

• When the efficacy and safety profiles are
  almost identical, use the less expensive
  alternative
• Quinolones
• Cephalosporins
• Cabapenems
• Echinocandins

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Empiric broad-spectrum antibiotic Rx,then
streamline

• Empiric, i.e before the diagnosis is determined
• Must acknowledge the MDRO epidemic
• vs gpc, gnr, anaerobes, fungi
• Then, streamline (a.k.a. de-escalate) based on
  CS

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When to Not Use in the First Place or When to
Discontinue Antibiotics Altogether?

• Asymptomatic UTI
• Viral URI
• Exacerbation of COPD?
• CHF, misdiagnosed as pneumonia
• CoNS bacteremia, when contamination more likely
  than true infection
• Duration? criteria to d/c

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Asymptomatic UTINicolle et al. Infectious
Diseases Society of America guidelines for the
diagnosis and treatment of asymptomatic
bacteriuria in adults. Clin Infect Dis
200540643-54

• Definition pyuria/bacteriuria, without Sx, with
  normal temperature and WBC
• Common

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Asymptomatic UTI
Nicolle et al. Clin Infect Dis 200540643-54
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Asymptomatic UTI
Boscia et al. JAMA 1987 2571067-71 Nordenstam
et al. NEJM 1986 3141152-6 Nicolle et al. NEJM
1983 369 1420-5 Ouslander et al. Ann Intern Med
1995122 749-54
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Mortality in patients with asymptomatic UTIs
treated with antimicrobial agents or placebo
Abrutyn, E. et. al. Ann Intern Med
1994120827-833
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• Practitioners do not feel comfortable ignoring
  bacteriuria once they are aware of its presence.
• Encourage physicians not to screen for
  asymptomatic bacteriuria
• U.S. Preventive Services Task Force. Screening
  for asymptomatic bacteriuria in adults U.S.
  Preventive Services reaffirmation recommendation
  statement. Ann Intern Med 200814943-7

36

• Increase adherence to non-treatment guidelines
• Gross, Patel. Reducing antibiotic overuse a
  call for a national performance measure for not
  treating asymptomatic bacteriuria. Clin Infect
  Dis 2007451335-7

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Asymtomatic UTIIs it applicable to catheter-
associated bacteriuria?

• Yes
• Cope et al. Inappropriate Treatment of
  Catheter-Associated Asymtomatic Bacteriuria in a
  Tertiary Care Hospital. Clin Infect Dis.
  2009481182-88
• Kunin. Editorial Commentary Catheter-Associated
  UTIs A Syllogism Compounded by a Questionable
  Dichotomy.
• Ibid 1189-90

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Viral URI Review of Acute Rhinosinusitis.
JAMA. 2009301(17)1798-1807

• How do you know its viral and not bacterial?
• Physical exam non-specific
• Temperature
• WBC
• Prevailing attitude of physicians and patients
• Take an antibiotic, just in case what if
• Changing paradigm, because of
• MDROs
• Side effects
• C. diff
• Other
• Recommendation Withhold AB for the first 10
  days

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Antibiotics for Treatment of Acute Maxillary
Sinusitis
JAMA 20082982487-96
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Cdc rx
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Cdc return to school letter
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• Materials order form
• http//www.cid.gov/ncidod/dbmd/antibiotic
  resistance/educatio.htm

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Exacerbation of COPD?Van Der Valk et al. Clin
Inf Dis 200439 980-6

• How do you know if its bacterial?
• Tough question, not adequately answered in the
  literature
• Antibiotics not unreasonable.
• 5 days should suffice

44
CHF, misdiagnosed as pneumonia

• How do you distinguish one from the other?
• HP, temperature, WBC, CXR, BNP, BioZ, cultures
  (sputum and blood), pneumococcal urine antigen
• The patient could have both

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Community-Acquired Pneumonia When to Begin
Antibiotics?

• The 2-4-6-8 hour rules
• IDSA/ATS Guidelines for CAP in Adults. Clin
  Infect Dis 2007 44 S27-72.
• CMS Specifications Manual For National Inpatient
  Quality Measures

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Timing of antibiotics for CAPControversy

• Earlier better than later
• Intuitive
• Data
• Embraced by CMS
• IDSA/ATS response
• Rebuts the data
• Points out the negative consequences of
  injudicious antibiotics
• Present state of affairs

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• IDSA/ATS Guidelines
• A problem of internal consistency is also
  present, because, in both studies 109, 264,
  patients who received antibiotics in the first 2
  h after presentation actually did worse than
  those who received antibiotics 24 h after
  presentation

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• For these and other
• reasons, the committee did not feel that a
  specific time window
• for delivery of the first antibiotic dose should
  be recommended.
• However, the committee does feel that therapy
  should be administered as soon as possible after
  the diagnosis is considered likely.

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• Conversely, a delay in antibiotic therapy has
  adverse consequences in many infections. For
  critically ill, hemodynamically unstable
  patients, early antibiotic therapy should be
  encouraged, although no prospective data support
  this recommendation.

50

• Delay in beginning antibiotic treatment during
  the transition from the ED is not uncommon.
  Especially with the frequent use of once-daily
  antibiotics for CAP, timing and communication
  issues may result in patients not receiving
  antibiotics for 18 h after hospital admission.
  The committee felt that the best and most
  practical resolution to this issue was that the
  initial dose be given in the ED.

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• If antibiotics started,
• and patient doesnt have pneumonia
• discontinue them
• At once
• If continued, 5 days should suffice
• Dunbar et al. High-dose, short-course
  levofloxacin for community-acquired pneumonia a
  new treatment paradigm. Clin Infect Dis 2003
  3775260.
• Etc.

53
VAP Duration of Rx

• Shorter than longer
• Chastre et al. Comparison of 8 vs 15 days of
• antibiotic therapy for ventilator-associated
• pneumonia in adults a randomized trial.
• JAMA 2003 290258898.

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CoNS bacteremia

• How do you know if its real or contamination?
• Real
• Hospitalized, IV (phlebitis), fever,
  leukocytosis, multiple positive cultures
• Contamination
• Present on admission/no IV, no fever, no
  leukocytosis, few positive cultures/denominator

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Additional recommendations

• SCIP
• C.difficile
• Pneumonia
• CAP
• HAP

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Surgical Care Improvement Project (SCIP)

• Antibiotics for surgical prophylaxis (Bratzler
  et al. Clin Infect Dis. 2004 Jun
  1538(12)1706-15)
• Which agent?
• Function of most common pathogen(s)
• Staph. aureus
• First generation cephalosporin
• If PCN-allergic
• If high prevalence of MRSA
• Anaerobes
• Cefoxitin
• When to start?
• 1 hour pre-op
• When to stop?
• 1 dose only
• Within 24 hours

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HAP
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Duration Criteria to d/c antibiotics

• By the numbers, e.g. 5, 7, 10, 14 days no!
• Empiric discontinuation, once temperature and WBC
  have normalized
• Notable exceptions
• Endocarditis
• Osteomyelitis
• Community-acquired pneumonia 5 days
• Healthcare-acquired pneumonia abbreviate
• Uncomplicated UTI 3 days
• Clin Infect Dis 19992974558

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Physician/administration approval and
notification

• Medical Executive Committee
• Physician champion
• Physicians

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Sample letter to physicians

• Dear Colleague,
• In an attempt to confront the MDRO
  (multi-drug resistant organism, e.g. MRSA) and C.
  difficile epidemics, our Hospital is initiating
  an Antibiotic Stewardship Program. Our goal is
  to promote judicious antibiotic use.
  Implementation will be through review of patients
  on antibiotics, then physician notification to
  consider Rx modifications. This has been
  approved by the Medical Executive Committee.

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Physician Response

• Bell-shaped curve
• Dr. D
• Dr. S
• Dr. C
• Dr. O
• Antibiotics viewed as drugs of fear
• Fear of omission
• Law suits
• Fear of commission
• Law suits

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Outcomes Measure Interventions

• patients reviewed
• interventions recommended
• Divided by patients of reviewed
• interventions accomplished
• Divided by recommended
• Change to avoid allergic reaction
• Drug-drug interactions addressed
• Change to different antibiotic based on CS
• Change dose
• IV-to-po switch
• Redundancy addressed
• Antibiotics discontinued altogether

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Outcomes Measure Interventions

• patients reviewed 500
• interventions recommended 45
• Divided by patients of reviewed 9
• interventions accomplished 38
• Divided by recommended 84
• Change to avoid allergic reaction 0
• Drug-drug interactions addressed 0
• Change to different antibiotic based on CS 8
• Change dose 0
• IV-to-po switch 24
• Redundancy addressed 0
• Antibiotics discontinued altogether 68

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OutcomesRates

• C. difficile
• MDRO
• MRSA
• VRE
• GNR
• ESBL
• CRE

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OutcomesNegative Consequences

• Keep a close eye out for any patient who suffers
  because of an antibiotic stewardship
  intervention, viz.
• relapse of infection
• from antibiotic deficiency

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Reporting the Outcomes

• Hospital
• PT Committee
• Infection Control Committee
• Medical Executive Committee
• MRSA Collaborative
• Federal Agencies
• JCAHO
• CMS
• Public relations
• Local newspaper

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Cost Implications

• Its the right thing to do, regardless of cost
  issues
• Antibiotic costs savings predicted/proven
• Administration happy
• Personnel needs to be recognized/compensated
• Pharmacist
• ID or other MD oversight
• Self-perpetuating

73
Results of an Antibiotic Intervention Program in
a University-Affiliated Teaching Hospital
Ruttimann al. Clin Infect Dis 2004 38348-56.
74
2008 Antibiotic Cost Per MonthMidwest Regional
Medical Center
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BREAK
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Vignettes

• Asymptomatic UTI
• Viral URI
• Exacerbation of COPD
• Pneumonia vs CHF
• Immunocompromised host with fever
• Antibiotic duration
• C. difficile
• SCIP

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Asymtomatic UTI

• An 83 yo woman suffers from dementia and resides
  in a nursing home. The NH staff is concerned
  about her increased confusion and decides to send
  her to the local ER. VS BP 140/90, P 90, RR
  16, T 98.6. PE WNL except for mild confusion.
  No Foley. WBC 10.1. U/A 5-10 WBC/hpf. Dx
  UTI. Rx Avelox. The following day her urine
  culture returns with E.coli, gt100K. Avelox is
  continued x 1 wk. She becomes more confused.
  And she develops C.diff antibiotic-associated
  colitis

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• Comments
• On occasion, sepsis can present with normal or
  low temperature and WBC, and with confusion
  However, she wasnt septic based on the normal BP
  and P
• An asymptomatic UTI does not need Rx.
• Avelox is not indicated for UTI.
• Quinolones can cause CNS problems
• All antibiotics can cause C.diff AAC.
• The elderly and NH residents are predisposed

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Antibiotic StewardshipAsymptomatic bacteriuria

• This patient appears to have asymptomatic
  bacteriuria which does not merit antibiotic Rx.
• Infectious Diseases Society of America
  Guidelines for the Diagnosis and Treatment of
  Asymptomatic Bacteriuria in Adults Clin Infect
  Dis 2005 40 64354

80
Viral URI

• A 72 yo diabetic man developed nasal congestion
  and cough productive of purulent sputum. He went
  to his local ER where the evaluation was
  noteworthy for a temperature of 99.6, normal
  respirations, mild tenderness to palpation and
  percussion over his sinuses, clear lungs, a WBC
  of 7.8 with 6 eosinophils and CXR showing
  chronic scarring. His blood sugar was 311. He
  was admitted. After a sputum was obtained for
  CS, he was started on Rocephin and Zithromax for
  possible community-acquired pneumonia. The
  sputum had gt25 epithelial cells and was rejected.
  The symptoms persisted for another 3 days.
  Levaquin was added. He developed C.diff
  antibiotic-associated colitis, his fifth episode.

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• Comments
• Great respect and extra attention must be given
  to immunocompromised hosts, e.g. diabetics.
• Yet even immunocompromised hosts can catch
  otherwise benign, self-limiting viral URIs for
  which antibiotics are not indicated.
• 99.6 isnt fever
• A reasonable clinical approach would be to d/c
  antibiotics and follow clinically, re-thinking
  their indication if the patient develops symptoms
  of a bacterial superinfection, e.g. fever.

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Antibiotic StewardshipViral URI

• This patient appears to have a viral URI which
  does not merit antibiotic Rx
• Review of Acute Rhinosinusitis. JAMA.
  2009301(17)1798-1807

83
Exacerbation of COPD

• Its February, and a 60 yo smoker with COPD
  developed worsening of his chronic cough and SOB.
  His sputum has become more copious, thicker,
  discolored and foul-smelling, and he has noted a
  fleck of blood. He has not had any chills or
  fever. On physical exam, he is receiving O2
  through nasal prongs. His respiratory rate is
  24/min and slightly labored. His temperature is
  99.1, BP 95/70, pulse 120. His breath sounds are
  distant and there are scattered ronchi and
  wheezes. The WBC is 11.1. A CXR shows emphysema
  and a faint haze at the bases interpreted as
  cannot rule out pneumonia.

84

• Although influenza and RSV has been reported
  in the community, rapid tests for influenza AB
  and RSV are negative.There are many PMNs and
  mixed flora on the sputum gram stain. It
  ultimately grows H. influenza and the
  pneumococcus (PCN MIC 1.0). He is admitted to
  hospital and is treated with Cipro.

85

• Comments
• Since its respiratory virus season, this is a
  good bet.
• Rapid tests have variable sensitivity. Go with
  the epidemiology
• Give an anti-influenza agent, ASAP
• While the H.flu and pneumococcus could represent
  otherwise benign colonization, either could be
  playing a pathogenic role.
• And colonization is the first step to infection,
  so why wait?
• Hes too fragile to risk withholding antibiotics.
• Use a respiratory quinolone, i.e. not cipro-, but
  rather levo- or moxi-
• Make sure he has received influenza and
  pneumococcal vaccines

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Antibiotic StewardshipCOPD exacerbation

• Recommendations
• Tamiflu
• Change from Cipro to Levaquin

87
Pneumonia vs CHF

• A 90 yo with a h/o CHF has become more short of
  breath over the past few days. There have been
  no fevers or chills. On physical exam the
  temperature is 97, RR 24, BP 160/100 and pulse
  80. Bibasilar rales are noted on auscultation.
  Theres a cardiac gallop. The CXR shows
  cardiomegaly and pulmonary congestion consistent
  with CHF, cannot rule out early pneumonia. The
  BNP is 1567. BioZ says CHF. He receives Lasix
  and improves. Rocephin and Zithromax were also
  started in the ER, for possible pneumonia.

88

• Comments
• CHF seems readily apparent.
• While pneumonia isnt entirely impossibleand he
  could have boththe potential side-effect of
  antibiotics dont seem worth the risk in this
  case.
• Blame the ER for having started them
• ER
• Hospitals front door, EMTALA
• Dx often uncertain
• ABs used liberally
• ABs can/should be d/cd promptly, once ID unlikely

89
Antibiotic Stewardship Pneumonia vs CHF

• Recommendation CHF is apparent, and
  pneumonia seems unlikely, so consider d/c
  antibiotics.

90
Immunocompromised Patient with Fever

• A 45 yo woman has fever complicating her
  metastatic breast cancer and its chemotherapy.
  She presents with chills and shortness of breath.
  Her temperature is 105, RR 32, BP 90/70, pulse
  130. Her lungs are clear. The WBC is 0.3.
  There are bilateral infiltrates on the CXR. She
  is started on Fortaz, Vancomycin, Zithromax,
  Diflucan and Zovirax.

91

• Comments Too complex to intervene.

92
Antibiotic Duration?

• A 92 yo nursing home resident (where C. diff has
  been epidemic) is transferred to the hospital for
  decreased mentation and poor intake. Her BMs are
  normal. On admission her temperature is 101 and
  the physical exam non-diagnostic. She has a 16K
  WBC and her creatinine is 3.1. There are 5-10
  WBC in the U/A and the CXR reads cannot R/O
  pneumonia. She is treated empirically with
  Rocephin, Levaquin and vancomycin. Cultures of
  urine and blood remain negative. There is no
  diarrhea to suspect C. diff. A repeat CXR shows
  no change. She promptly defervesces and her
  WBC has normalized when repeated at 48 hours.

93

• Comments
• The diagnosis is uncertain presumably
  infected, but source (i.e. site and pathogen)
  not defined.
• Whether she improved from the empiric antibiotics
  or not is also uncertain.
• Pneumonia the CXR often remains abnormal
  several weeks after the clinical syndrome has
  resolved
• Injudicious to continue ABs until CXR resolution
• She is at considerable risk for C. diff and other
  AB-associated problems.
• So it wouldnt be unreasonable to d/c
  antibiotics.

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Antibiotic StewardshipAntibiotic Duration

• Recommendation Consider d/cing antibiotics,
  as the temperature and WBC have normalized.

95
C. difficile

• An 85 yo WF is admitted from the NH with C.
  difficile. Her temperature is 102 and her WBC
  is 65,000. She receives Vanco IV and po, Flagyl
  I V and po, Immodium, probiotics and Rocephin.

96

• Comments Refer to the C. diff guidelines
• Continue po Flagyl
• d/c other antibiotics
• d/c Immodium

97
SCIP

• An 85 yo WM is admitted to the hospital for a hip
  fracture. He undergoes ORIF and receives
  peri-operative antibiotics. These are continued
  indefinitely. His wound is clean and he has a
  normal temperature and WBC.

98

• Comments Refer to SCIP guidelines
• Recommend d/c antibiotics post-op

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Antibiotic StewardshipSummary/Implementation

• Decide if you want to do it.
• Decide whos going to do it.
• Must have a PHYSICIAN CHAMPION
• Seek approval from the Medical Executive
  Committee.
• Decide upon form of communication phone call
  vs notation in chart.
• Send an introductory/explanatory letter to the
  Medical Staff.
• Do it.
• Measure the results.
• Present and discuss results.
• Review and improve.

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Questions/Discussion